Lin Zhoumeng, Dodd Celia A, Filipov Nikolay M
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA.
Neurotoxicol Teratol. 2013 Sep-Oct;39:26-35. doi: 10.1016/j.ntt.2013.06.002. Epub 2013 Jun 14.
Excessive exposure to the widely used herbicide atrazine (ATR) affects several organ systems, including the brain, where neurochemical alterations reflective of dopamine (DA) circuitry perturbation have been reported. The present study aimed to investigate effects of short-term oral exposure to a dose-range (0, 5, 25, 125, or 250 mg/kg) of ATR on behavioral, neurochemical, and molecular indices of toxicity in adult male C57BL/6 mice. The experimental paradigm included open field, pole and grip tests (day 4), novel object recognition (NOR) and forced swim test (FST; day 9), followed by tissue collection 4h post dosing on day 10. After 4 days of exposure, ATR decreased locomotor activity (≥125 mg/kg). On day 9, ATR-exposed mice exhibited dose-dependent decreased performance in the NOR test (≥25 mg/kg) and spent more time swimming and less time immobile during the FST (≥125 mg/kg). Neurochemically, short-term ATR exposure increased striatal DA and DA turnover (its metabolite homovanillic acid [HVA] and the HVA/DA ratio; ≥125 mg/kg). In addition, ATR exposure increased the levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum (≥125 mg/kg) and it also increased DA turnover (≥125 mg/kg), 5-HIAA (125 mg/kg), and norepinephrine (≥125 mg/kg) levels in the prefrontal cortex. In the hippocampus, the only effect of ATR was to increase the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG; 250 mg/kg). At the molecular level, the expression of key striatal (protein) or nigral (mRNA) markers associated with nigrostriatal DA function, such as tyrosine hydroxylase, DA transporter, vesicular monoamine transporter 2, and DA receptors, was not affected by ATR. These results indicate that short-term ATR exposure targets multiple monoamine pathways at the neurochemical level, including in the striatum, and induces behavioral abnormalities suggestive of impaired motor and cognitive functions and increased anxiety. Impaired performance in the NOR behavioral test was the most sensitive endpoint affected by ATR; this should be taken into consideration for future low-dose ATR studies and for the assessment of risk associated with overexposure to this herbicide.
过度接触广泛使用的除草剂阿特拉津（ATR）会影响多个器官系统，包括大脑，据报道，大脑中存在反映多巴胺（DA）回路紊乱的神经化学改变。本研究旨在调查成年雄性C57BL/6小鼠短期口服剂量范围（0、5、25、125或250 mg/kg）的ATR对行为、神经化学和分子毒性指标的影响。实验范式包括旷场试验、爬杆和抓握试验（第4天）、新物体识别试验（NOR）和强迫游泳试验（FST；第9天），随后在第10天给药后4小时收集组织。暴露4天后，ATR降低了运动活性（≥125 mg/kg）。在第9天，暴露于ATR的小鼠在NOR试验中表现出剂量依赖性下降（≥25 mg/kg），并且在FST期间游泳时间增加，不动时间减少（≥125 mg/kg）。神经化学方面，短期ATR暴露增加了纹状体中的DA及其代谢率（其代谢产物高香草酸 [HVA] 和HVA/DA比值；≥125 mg/kg）。此外，ATR暴露增加了纹状体中血清素代谢产物5-羟吲哚乙酸（5-HIAA）的水平（≥125 mg/kg），并且还增加了前额叶皮质中的DA代谢率（≥125 mg/kg）、5-HIAA（125 mg/kg）和去甲肾上腺素（≥125 mg/kg）水平。在海马体中，ATR的唯一作用是增加去甲肾上腺素代谢产物3-甲氧基-4-羟基苯乙二醇（MHPG；250 mg/kg）。在分子水平上，与黑质纹状体DA功能相关的关键纹状体（蛋白质）或黑质（mRNA）标志物，如酪氨酸羟化酶、DA转运体、囊泡单胺转运体2和DA受体的表达，不受ATR影响。这些结果表明，短期ATR暴露在神经化学水平上靶向多个单胺途径，包括纹状体中的途径，并诱导提示运动和认知功能受损以及焦虑增加的行为异常。NOR行为试验中的表现受损是受ATR影响最敏感的终点；在未来的低剂量ATR研究以及评估与过度接触这种除草剂相关的风险时应考虑到这一点。
